This invention pertains to immunoconjugates and their use in different indications. In particular, the present invention relates to immunoconjugates, the delivery of their effector molecule(s) to target sites and the site specific release of the effector molecule(s) in, at or near target cells, tissues and organs. More particularly, the present invention relates to immunoconjugates comprising one or more syndecan-1 targeting agent and highly potent effector molecules, which are attached to the targeting agent. The effector molecule is activated by cleavage/dissociation from the targeting agent portion of the immunoconjugate in, at or near the target cells, tissues or organs.
The publications and other materials, including patents, used herein to illustrate the invention and, in particular, to provide additional details respecting the practice are incorporated by reference. For convenience, the publications are referenced in the following text by author and date and are listed alphabetically by author in the appended bibliography.
A substantial body of research has concentrated on the development of systems in which an effector agent can be selectively delivered to a desired location or cell population, i.e., a system for a more targeted treatment of ailments with fewer toxic side effects. In spite of considerable progress that has been achieved, many of those delivery systems for the treatment of various diseases, for example, the treatment of cancer, are still often ineffective or subject the patient to considerable risk.
Immunoconjugates comprise at least one targeting agent attached to at least one effector molecule. Such immunoconjugates can be categorized according to their effector molecules into, for example, drug immunoconjugates, immunotoxin conjugate and radioimmunoconjugates (Payne, 2003).
Efficiency in killing cells is one key factor in the usefulness of an immunoconjugate. Efficiency can be influenced by the potency of the effector molecule (Blättler and Chari, 2001), by the ability of the effector to retain its potency (Chari et al., 1995; Liu et al., 1996; Ojima et al., 2002; Senter et al., 2002 and Sievers and Linenberger, 2001), By the tumor accessibility (Charter, 2001), by the level of expression of the target antigen on the target cell, targeting agent affinity, and by the ability of the target cell to internalize the immunoconjugate (Wargalla, 1989). In the initial development period of immunoconjugates, the efficiencies of conjugates having a drug as an effector molecule often were disappointing compared to the free drug.
In response, immunoconjugates with highly cytotoxic effector toxin molecules were constructed. However, while the efficiencies of this new generation of immunoconjugates were much improved, they were often immunogenic in humans, inducing neutralizing antibodies both to the toxin protein and to the mouse monoclonal antibody. In response, “humanized” antibodies conjugated to nonimmunogenic effector molecules were developed (Payne, 2003).
In the context of both highly cytotoxic drugs and toxins conjugated to a targeting agent, systemic toxicity has to be considered. If the cytotoxic drug or the toxin is highly cytotoxic, the immunoconjugate has to reach its target site without adversely affecting the host on its way. Accordingly, if the immunoconjugate circulates, for example, in the bloodstream to reach its target site, then this should occur without a substantial release of active drug. Thus, ideally, a highly cytotoxic drug or toxin of an immunoconjugate is only activated upon reaching its target.
Specificity is another factor critical for the usability of an immunoconjugate. The immunoconjugate has to be able to selectively interact with the target cells. Particularly for in vivo applications, it is critical that the immunoconjugate does not have substantial adverse effects on essential non-target cells. Thus, both the cellular target of the immunoconjugate and the targeting agent of the immunoconjugate have to be carefully selected to ensure specificity (Blättler and Chari, 2001).
It has also been considered important that immunoconjugates comprising targeting antibodies demonstrate pharmacokinetic and tissue distribution characteristics similar to those of corresponding antibodies (Xie, 2003).
First successes have been achieved with immunoconjugates. For example, MYLOTARG, a conjugate of an anti-CD33 humanized monoclonal antibody and the highly cytotoxic DNA-damaging agent calicheamicin, has been recently approved by the FDA as the first drug immunoconjugate for clinical treatment of certain indications of myeloid leukemia (Bross, 2001; Hamann, 2002; Dowell, 2001).
However, there remains a need to develop effective immunoconjugates for a wide array of indications.